Naftopidil is an α1 adrenoceptor antagonist having high selectivity to α1A−/α1D receptor, and is clinically used as a therapeutic drug for prostatomegaly and hypertension (Takei R, et al., Jpn J Pharmacol 1999; 79:447-454). The chemical name of naftopidil is ((±)-1-[4-(2-methoxyphenyl)piperazinyl]-3-(1-naphthyloxy)propan-2-ol, which is a substance represented by the following formula and created by Boehringer•Mannheim (now Roche) in Germany

It was first disclosed in JP-A-50-121286 together with a pharmaceutically acceptable salt thereof. In recent years, it has been reported that naftopidil also has an anticancer action. For example, naftopidil was shown to inhibit the growth of prostate cancer cell by discontinuing the G1 phase of the cell cycle (Hori Y, et al., Cancer Prev Res (Phila) 2011; 4:87-96; Kanda H, et al., Int J Cancer 2008; 122:444-451).
In an earlier study, the present inventors reported that naftopidil decreases the cell survival rate of the cell lines of bladder cancer, prostate cancer and kidney cancer (Gotoh A, et al., “Anti-tumor action of a1-adrenoceptor blockers on human bladder, prostate, and kidney cancer cells.” Pharmacology 2012; 90:242-246). Naftopidil also induces apoptosis in the cell line of malignant mesothelioma. From these findings, the possibility of naftopidil being promising as an anti-cancer agent is considered. However, the mechanism of the anticancer action of naftopidil contains aspects yet to be clarified.
α1-adrenoceptor is divided into 3 subtypes of α1A-, α1B- and α1D-. They conjugate with Gq/11 protein, activate phospholipase C and then activate protein kinase C (PKC) (Brede M, et al., Biol Cell 2004; 96:343-348; Kaumann A J, and Molenaar P, Naunyn Schmiedebergs Arch Pharmacol 1997; 355:667-681; Zhong H, and Minneman K P, Eur J Pharmacol 1999; 375:261-276). Accordingly, naftopidil inhibits PKC by inhibiting α1-adrenoceptor. However, GF109203X, which is a PKC inhibitor, does not potentiate apoptosis of malignant mesothelioma induced by naftopidil, but conversely weakened the effect of naftopidil (data not shown). Furthermore, the growth of malignant mesothelioma cells was promoted by knocking-down α1D-adrenoceptor (data not shown). These results suggest that naftopidil induces apoptosis of malignant mesothelioma cells by a mechanism different from the inhibition of α1-adrenoceptor. As the situation stands, however, the mechanism thereof has not been elucidated yet.